Acyl CoA or diacylglycerol acyltransferase (“DGAT”) is the enzyme that catalyzes the last stage of the glyceryl 3-phosphate path, and plays a role of synthesizing triglycerides using 1,2-diacylglycerol and fatty acyl CoA as a substrate. For the biosynthesis of triglycerides, glycerol 3-phosphate path (liver and adipose tissue, etc.), and the mono-acylglycerol (intestinal epithelial cells of the small intestine) are used.
Recently, Gladstone Institute of Cardiovascular Diseases in USA reported evidence that according to DGAT function researche using the DGAT-1 deficient mouse, the DGAT-1 deficient mouse had effectively inhibited diet-induced obesity by administration of a high fat diet, and increased sensitivity to insulin and leptin, thus indicating improved glucose metabolism. The follow-up researche reported that in insulin-sensitive tissues like fat tissues, skeletal muscles, liver, and pancreatic beta cells, selective inhibition of DGAT, which is the catalytic enzyme of the biosynthesis process of triglycerides, was effective in the prevention and treatment of obesity and type 2 diabetes (Chen H C, et al., Trends Cardiovasc. Med., 10, 188-192, 2000; Farese Jr. et al., Curr. Opin. Lip idol., 11, 229-234, 2000; A. Subauste et. al., Current Drug Target-Immun, Endocrine & Metabol Disorders, 3, 263-270, 2003; Y. Yu et. al. Anals of Medicine, 36, 252-261).
When the activity of DGAT is inhibited, the enzyme catalytic reaction of DGAT for the synthesis of triglycerides is blocked or has reduced synthetic reaction efficiency. By inhibiting biosynthesis of the triglycerides via the inhibition of DGAT which is the final stage in the triglyceride synthesis, accumulation of fat in the fat cells decrease with the size of the fatty cells reduced, and energy consumption increased due to increasing momentum, coupled with the increased expression of the uncoupling protein, and accordingly, high fat-induced weight gains are suppressed. (Smith SJ. et al., Nature Genetics, 25, 87-90, 2000; Chen et al., J Clin Invest., 109 (8), 1049-1055, 2002; Chen et al., J Clin Invest., 111, 1715-1722, 2003; Chen et al. Am. J. Physiol. Endocrono I. Metab., 284, E213-218, 2003).
In addition, DGAT inhibition is known to bring about improved insulin resistance (IR), by suppressing fat accumulation in skeletal muscle, liver, pancreas and other non-adipose tissue.
That is, in response to stimuli by insulin, cells have reduced inhibitory phosphorylation at the serine site of insulin receptor substance-1 (IRS-1) and increased phosphorylation at the tyrosine sites, thus have increased number of GLUT-4, the sugar transporter, via the activation of insulin signaling along phosphatidylinositol-3 kinase (PI-3K), protein kinase B, Akt (PKB), protein kinase C (PK0), etc.
With the inhibition of DGAT activity in the cells, activities of PI-3K, PKB, and PKC increases, thus causing increased number of GLUT-4 ectocytosized to the membrane, and finally increasing the number of cells introduced into cells. That is, DGAT inhibition increases sensitivity to insulin (Chen et al., Arterioscler Thromb Vase Biol. 25 (3), 482-486, 2005; Chen et al., J Clin Invest. 111 (11), 1715-22, 2003; Chen et al., J Clin Invest. 109 (8), 1049-1055, 2002; Chen et al., Diabetes. 51 (11), 3189-3195, 2002; Subauste and bur ant., Curr Drug Targets Immune Endocr Metabol Disord. 3 (4), 263-270, 2003). As the direct linkage between DGAT inhibition and overcoming insulin resistance is elucidated, it is also understood that the DGAT inhibition can be applicable as a treatment target for type 2 diabetes, the abnormal condition caused due to insulin resistance that blocks glucose absorption, even with normal insulin secretion.
The known compounds as the DGAT enzyme inhibitors include biphenyl-4-yl-carbonyl-amino acid derivatives (WO2006044775, Bayer Pharmaceuticals Corp), urea derivatives (WO2006019020, WO2006004200, Sankyo Co), pyrrole carboxylic acid derivatives (JP05213985A, Mitsubishi Kasei Corp, Japan), and phosphonic acid ester derivative (JP2004067635A—Otsuka Pharmaceut Factory INC, Japan), etc. On the other hand, DGAT enzyme inhibitors from natural products of ginseng polyacetylenes (Korea Patent No. 0460438, Lee et al. Planta Med. 70, 179-200, 2004), quinolone alkaloid, tanshinones, prenyl flavonoids) isolated from evodia, salvia, and saphora (Korea Patent No. 0577320, Ko et al., Arch. Phar. Res. 25, 446-448, 2002, Korea Patent No. 0507989).
In addition, the Omura research group of the Kitasato Institute (Japan) reported inhibitor such as roselipins (U.S. Pat. No. 6,432,682 (2002), U. S. Pat. No. 6,608,185 (2003)), cochlioqui none A and Al, I. Antibiot., 56,: 967, 2003; J. Antibiot., 57, 59, 2004), amidepsines and xanthohumols, and eicosapentaenoic acid, 2-bromooctanoate, and niacin (Rustan et al., J. Lipid. Res., 29, 1417-1426, 1988, Ganji et al. J. Lipid. Res., 45, 1835-1845).